Carbamoyl-type benzofuran derivatives

1. A carbamoyl-type benzofuran derivative of the formula [1]:

wherein Ring Z is a group of the formula:

A is a single bond or a group of the formula: —NH—;

Y is a lower alkylene group, a cycloalkanediyl group, a phenyl group or a saturated heterocyclic group;

R 4 and R 5 are the same or different and each is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted saturated heterocyclic group, or R 4 and R 5 combine together at the ends to form an optionally substituted nitrogen-containing saturated heterocyclic group along with the adjacent nitrogen atom;

R 1 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cyano group, or an amino group optionally substituted by 1 to 2 lower alkyl groups;

Ring B of the formula:

is an optionally substituted benzene ring; and

R 3 is a hydrogen atom or a lower alkyl group,

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein Ring Z is a group of the formula:

3. The compound according to claim 2 , wherein the “optionally substituted lower alkyl group” for R 4 or R 5 is an unsubstituted lower alkyl group, a lower alkyl group substituted by an amino group optionally substituted by 1 to 2 lower alkyl groups, a lower alkyl group substituted by a hydroxyl group, a lower alkyl group substituted by a lower alkoxy group or a lower alkyl group substituted by a pyridyl group;

the “optionally substituted saturated heterocyclic group” for R 4 or R 5 is tetrahydropyranyl;

the “optionally substituted nitrogen-containing saturated heterocyclic group” formed from R 4 , R 5 and the adjacent nitrogen atom, when R 4 and R 5 combine together at the ends, is a pyrrolidinyl group, a morpholinyl group, a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, a pyrrolidinyl group substituted by a hydroxyl group, a thiomorpholinyl group, a piperidyl group, a piperidyl group substituted by a hydroxyl group, a piperazinyl group substituted by a hydroxy-lower alkyl group, a piperidyl group substituted by a hydroxy-lower alkyl group, a piperazinyl group substituted by a lower alkyl group, a pyrrolidinyl group substituted by a lower alkoxycarbonylamino group, a piperidyl group substituted by an amino group optionally substituted by 1 to 2 lower alkyl groups, an oxopyrrolidinyl group, an oxomorpholinyl group, an oxothiomorpholinyl group, an oxopiperidyl group, an oxopiperazinyl group, or a piperidyl group substituted by a lower alkoxycarbonyl group; and

the “saturated heterocyclic group” for Y is a piperidyl group.

4. The compound according to claim 3 , wherein Ring B is a benzene ring optionally substituted by one or two groups selected independently from a halogen atom, an optionally substituted lower alkyl group, a hydroxy group, an optionally substituted lower alkoxy group, an oxy group substituted by an optionally substituted saturated heterocyclic group, a substituted carbonyl group, an optionally substituted amino group, a nitro group, a cyano group, a 4,5-dihydroxazolyl group and a group of the formula:

5. The compound according to claim 4 , wherein the “optionally substituted lower alkyl group” as a substituent for Ring B is a lower alkyl group optionally substituted by a group selected from the following:

(1) a lower alkoxycarbonyl group,

(2) a carboxyl group,

(3) a carbamoyl group optionally substituted by 1 to 2 groups selected from (a) a lower alkyl group, (b) a lower alkoxy-lower alkyl group, (c) a hydroxy-lower alkyl group, (d) an aminoalkyl group optionally substituted by 1 to 2 lower alkyl groups, and (e) a lower alkoxy group,

(4) a carbonyl group substituted by a morpholinyl group,

(5) a piperidylcarbonyl group substituted by a hydroxy-lower alkyl group,

(6) a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl group,

(7) a carbonyl group substituted by a hydroxyl group-substituted piperidyl group,

(8) a hydroxyl group, and

(9) a pyrrolidinylcarbonyl group;

the “optionally substituted lower alkoxy group” as a substituent for Ring B is a lower alkoxy group optionally substituted by a group selected from the following:

(1) a carboxyl group,

(2) a lower alkoxycarbonyl group,

(3) a lower alkoxy group,

(4) a hydroxyl group,

(5) an aminooxy group optionally substituted by 1 to 2 lower alkoxycarbonyl groups,

(6) a lower alkoxy group substituted by a lower alkoxy group,

(7) a carbonyl group substituted by a group selected from morpholinyl group, a piperidyl group or a pyrrolidinyl group,

(8) a carbonyl group substituted by a hydroxypiperidyl group,

(9) a piperidylcarbonyl group substituted by a hydroxy-lower alkyl group,

(10) a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl group,

(11) a carbonyl group substituted by a lower alkyl-piperazinyl group,

(12) an amino group optionally substituted by 1 to 2 groups selected from (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanoyl group,

(13) a carbamoyl group optionally substituted by 1 to 2 groups selected from (a) a lower alkyl group, (b) a lower alkoxy-lower alkyl group, (c) a hydroxy-lower alkyl group, and (d) a lower alkyl group substituted by an amino group optionally substituted by 1 to 2 lower alkyl groups; and

(14) a group of the formula:

—O—NH—C(═NH)NH 2 ;

the “oxy group substituted by an optionally substituted saturated heterocyclic group” as a substituent for Ring B is an oxy group substituted by a saturated heterocyclic group optionally substituted by an aromatic hydrocarbon group;

the “substituted carbonyl group” as a substituent for Ring B is a carbonyl group substituted by a group selected from the following:

(1) a lower alkoxy group,

(2) a hydroxyl group,

(3) an amino group optionally substituted by 1 to 2 groups selected from (a) a lower alkyl group, (b) a lower alkoxy group, (c) a lower alkoxy-lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a lower alkyl group substituted by an amino group optionally substituted by 1 to 2 lower alkyl groups, (f) a lower alkyl group substituted by an aromatic hydrocarbon group, and (g) a lower alkyl group substituted by a pyridyl group,

(4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group,

(5) a hydroxypiperidyl group,

(6) a piperidyl group substituted by a hydroxy-lower alkyl group,

(7) a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and

(8) a lower alkyl-piperazinyl group;

the “optionally substituted amino group” as a substituent for Ring B is an amino group optionally substituted by 1 to 2 groups selected from the following:

(1) a lower alkyl group,

(2) a lower alkoxy-lower alkyl group,

(3) a hydroxy-lower alkyl group,

(4) a lower alkanoyl group,

(5) a lower alkoxy-lower alkanoyl group,

(6) a hydroxy-lower alkanoyl group,

(7) a lower alkanoyl group substituted by a lower alkanoyloxy group,

(8) a lower alkanoyl group substituted by an amino group optionally substituted by 1 to 2 groups selected from (a) a lower alkyl group and (b) a lower alkanoyl group,

(9) a lower alkoxycarbonyl group,

(10) a lower alkoxycarbonyl group substituted by an aromatic hydrocarbon group,

(11) a carbamoyl group substituted by 1 to 2 lower alkyl groups,

(12) a lower alkylsulfonyl group, and

(13) a lower alkylsulfonyl group substituted by a morpholinyl group.

6. The compound according to claim 5 , wherein Ring B is an unsubstituted benzene ring.

7. The compound according to claim 5 , wherein Ring Z is a group of the formula:

the formula:

R 1 is a halogen atom or a lower alkyl group;

R 2 is a group selected from the following:

A) a hydrogen atom, a cyano group, an amino group optionally substituted by 1 to 2 lower alkyl groups, a hydroxy group;

B) a lower alkyl group optionally substituted by a group selected from the following:

(1) a lower alkoxycarbonyl group,

(2) a carboxyl group,

(3) a carbamoyl group optionally substituted by 1 to 2 groups selected from (a) a lower alkyl group, (b) a lower alkoxy-lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, (d) a lower alkyl group substituted by an amino group optionally substituted by 1 to 2 lower alkyl groups, and (e) a lower alkoxy group,

(4) a carbonyl group substituted by a morpholinyl group,

(5) a piperidylcarbonyl group substituted by a hydroxy-lower alkyl group,

(6) a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl group,

(7) a carbonyl group substituted by a hydroxyl group-substituted piperidyl group,

(8) a hydroxyl group; and

(9) a pyrrolidinylcarbonyl group;

C) a lower alkoxy group optionally substituted by a group selected from the following:

(1) a carboxyl group,

(2) a lower alkoxycarbonyl group,

(3) a lower alkoxy group,

(4) a hydroxyl group,

(5) an aminooxy group optionally substituted by 1 to 2 lower alkoxycarbonyl groups,

(6) a lower alkoxy group substituted by a lower alkoxy group,

(7) a carbonyl group substituted by a group selected from a morpholinyl group, a piperidyl group or a pyrrolidinyl group,

(8) a carbonyl group substituted by a hydroxypiperidyl group,

(9) a piperidylcarbonyl group substituted by a hydroxy-lower alkyl group,

(10) a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl group,

(11) a carbonyl group substituted by a lower alkyl-piperazinyl group,

(12) an amino group optionally substituted by 1 to 2 groups selected from (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and(c) a lower alkanoyl group,

(13) a carbamoyl group optionally substituted by 1 to 2 groups selected from (a) a lower alkyl group, (b) a lower alkoxy-lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkyl group substituted by an amino group optionally substituted by 1 to 2 lower alkyl groups, and

(14) a group of the formula:

—O—NH—C(═NH)NH 2 ; or

D) a carbonyl group substituted by a group selected from the following:

(1) a lower alkoxy group,

(2) a hydroxyl group,

(3) an amino group optionally substituted by 1 to 2 groups selected from (a) a lower alkyl group, (b) a lower alkoxy group, (c) a lower alkoxy-lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a lower alkyl group substituted by an amino group optionally substituted by 1 to 2 lower alkyl groups, (f) a lower alkyl group substituted by an aromatic hydrocarbon group, and (g) a lower alkyl group substituted by a pyridyl group,

(4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group,

(5) a hydroxypiperidyl group,

(6) a piperidyl group substituted by a hydroxy-lower alkyl group,

(7) a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and

(8) a lower alkyl-piperazinyl group;

A is a single bond; and

R 3 is a hydrogen atom.

8. The compound according to claim 7 , wherein R 2 is a group selected from the following:

(1) a hydrogen atom,

(2) a cyano group,

(3) an amino group optionally substituted by 1 to 2 lower alkyl groups,

(4) a hydroxyl group,

(5) a lower alkoxy group,

(6) a lower alkoxy group substituted by a lower alkoxy group,

(7) a lower alkoxy group substituted by a hydroxyl group,

(8) a lower alkoxy group substituted by an amino group optionally substituted by 1 to 2 lower alkyl groups,

(9) a lower alkoxycarbonyl group,

(10) a carboxyl group,

(11) a carbonyl group substituted by an amino group optionally substituted by 1 to 2 groups selected from (a) lower alkyl group, (b) a hydroxy-lower alkyl group, (c) a lower alkoxy-lower alkyl group, and (d) a lower alkyl group substituted by an amino group optionally substituted by 1 to 2 lower alkyl groups,

(12) a morpholinylcarbonyl group, a pyrrolidinylcarbonyl group, a piperidylcarbonyl group or a thiomorpholinylcarbonyl group,

(13) a piperidylcarbonyl group substituted by a hydroxy-lower alkyl group, or a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl group,

(14) a lower alkyl group,

(15) a lower alkyl group substituted by a lower alkoxycarbonyl group,

(16) a carboxy-lower alkyl group,

(17) a lower alkyl group substituted by a carbamoyl group optionally substituted by 1 to 2 groups selected from (a) a lower alkyl group, (b) a hydroxy-lower alkyl group, (c) a lower alkoxy-lower alkyl group, and (d) a lower alkyl group substituted by an amino group optionally substituted by 1 to 2 lower alkyl groups,

(18) a lower alkyl group substituted by a morpholinylcarbonyl group,

(19) a lower alkyl group substituted by a piperidylcarbonyl group substituted by a hydroxy-lower alkyl group, or a lower alkyl group substituted by a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl group,

(20) a hydroxy-lower alkyl group, and

(21) a lower alkyl group substituted by a pyrrolidinylcarbonyl group.

9. The compound according to claim 7 , wherein R 2 is a group selected from the following:

(1) a hydrogen atom,

(2) a carbonyl group substituted by an amino group optionally substituted by 1 to 2 groups selected from (a) a lower alkyl group and (b) a lower alkoxy-lower alkyl group,

(3) a lower alkoxycarbonyl group,

(4) a morpholinylcarbonyl group, a pyrrolidinylcarbonyl group, a piperidylcarbonyl group or a thiomorpholinylcarbonyl group,

(5) a lower alkyl group substituted by a carbamoyl group substituted by 1 to 2 lower alkyl groups,

(6) a carboxy-lower alkyl group,

(7) a lower alkyl group substituted by a morpholinylcarbonyl group,

(8) a hydroxy-lower alkyl group,

(9) a lower alkyl group substituted by a pyrrolidinylcarbonyl group, and

(10) a lower alkyl group substituted by a carbamoyl group optionally substituted by 1 to 2 groups selected from (a) a lower alkyl group substituted by an amino group optionally substituted by 1 to 2 lower alkyl groups and (b) lower alkyl group.

10. The compound according to claim 7 , wherein R 2 is a group selected from the following:

(1) a hydrogen atom,

(2) a hydroxy-lower alkyl group,

(3) a carboxy-lower alkyl group,

(4) a lower alkoxy group substituted by a lower alkoxy group;

(5) a carbonyl group substituted by a group selected from (a) an amino group optionally substituted by 1 to 2 lower alkyl groups, and (b) a morpholinyl group;

(6) a carbamoyl group substituted by 1 to 2 groups selected from (a) a lower alkoxy-lower alkyl group and (b) a lower alkyl group;

(7) a lower alkyl group substituted by a carbamoyl group substituted by 1 to 2 groups selected from (a) a lower alkoxy-lower alkyl group and (b) a lower alkyl group;

(8) a carbamoyl group substituted by 1 to 2 groups selected from (a) a lower alkyl group substituted by an amino group optionally substituted by 1 to 2 alkyl groups and (b) a lower alkyl group,

(9) a lower alkyl group substituted by a carbamoyl group substituted by 1 to 2 groups selected from (a) an amino-lower alkyl group optionally substituted 1 to 2 alkyl groups and (b) a lower alkyl group,

(10) a lower alkyl group substituted by a pyrrolidinylcarbonyl group; and

(11) a carbamoyl-lower alkyl group optionally substituted by 1 to 2 groups selected from (a) a lower alkyl group substituted by an amino group optionally substituted by 1 to 2 lower alkyl groups and (b) a lower alkyl group.

11. A compound of the formula:

wherein X is a group of the formula: —N═ or —CH═;

A is a single bond or a group of the formula: —NH—;

Y is a lower alkylene group, a cycloalkanediyl group, a phenyl group or a saturated heterocyclic group;

R 6 is a protecting group for carboxyl group;

R 1 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cyano group, or an amino group optionally substituted by 1 to 2 lower alkyl groups;

Ring B of the formula:

is an optionally substituted benzene ring; and

R 3 is a hydrogen atom or a lower alkyl group.

12. A compound of the formula:

wherein X is a group of the formula: —N═ or —CH═;

A is a single bond or a group of the formula: —NH—;

Y is a lower alkylene group, a cycloalkanediyl group, a phenyl group or a saturated heterocyclic group;

R 1 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cyano group, or an amino group optionally substituted by 1 to 2 lower alkyl groups;

Ring B of the formula:

is an optionally substituted benzene ring; and R 3 is a hydrogen atom or a lower alkyl group.

13. The compound according to claim 11 or 12 , wherein the formula:

14. The compound according to claim 5 , wherein Ring Z is a group of the formula:

R 1 is a halogen atom;

R 3 is a hydrogen atom;

the formula:

R 2 is a carbonyl group substituted by a group selected from the following:

(1) a lower alkoxy group,

(2) a hydroxyl group,

(3) an amino group optionally substituted by 1 to 2 groups elected from (a) a lower alkyl group, (b) a lower alkoxy group, (c) a lower alkoxy-lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a lower alkyl group substituted by an amino group optionally substituted by 1 to 2 lower alkyl groups, (f) a lower alkyl group substituted by an aromatic hydrocarbon group, and (g) a lower alkyl group substituted by a pyridyl group,

(4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group,

(5) a hydroxypiperidyl group,

(6) a piperidyl group substituted by a hydroxy-lower alkyl group,

(7) a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and

(8) a lower alkyl-piperazinyl group;

A is a single bond;

Y is a cyclohexanediyl group; and

R 4 and R 5 are independently a lower alkyl group, or R 4 , R 5 and the adjacent nitrogen atom, when R 4 and R 5 combine together at the ends, form a pyrrolidinyl group, a morpholinyl group, a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, a pyrrolidinyl group substituted by a hydroxyl group, a thiomorpholinyl group, a piperidyl group, a piperidyl group substituted by a hydroxyl group, a piperazinyl group substituted by a hydroxy-lower alkyl group, a piperidyl group substituted by a hydroxy-lower alkyl group, a piperazinyl group substituted by a lower alkyl group, a pyrrolidinyl group substituted by a lower alkoxycarbonylamino group, a piperidyl group substituted by an amino group optionally substituted by 1 to 2 lower alkyl groups, an oxopyrrolidinyl group, an oxomorpholinyl group, an oxothiomorpholinyl group, an oxopiperidyl group, an oxopiperazinyl group, or a piperidyl group substituted by a lower alkoxycarbonyl group.

15. The compound according to claim 14 , wherein R 2 is a carbonyl group substituted by a group selected from the following:

(1) an amino group optionally substituted by 1 to 2 groups selected from (a) a lower alkyl group, (b) a lower alkoxy group, (c) a lower alkoxy-lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a lower alkyl group substituted by an amino group optionally substituted by 1 to 2 lower alkyl group, (f) a lower alkyl group substituted by an aromatic hydrocarbon group, and (g) a lower alkyl group substituted by a pyridyl group, and

(2) a morpholin-4-yl group, a pyrrolidin-1-yl group, a piperidin-1-yl group a piperazin-1-yl group or a thiomorpholin-4-yl group;

R 4 and R 5 are independently a lower alkyl group, or

R 4 , R 5 and the adjacent nitrogen atom, when R 4 and R 5 combine together at the ends, form a pyrrolidin-4-yl group.

16. The compound according to claim 15 , wherein the formula:

R 2 is a carbonyl group substituted by a group selected from the following:

(1) an amino group optionally substituted by 1 to 2 groups selected from (a) a lower alkyl group and (b) a lower alkoxy-lower alkyl group, and

(2) a morpholin-4-yl group.

17. Methyl 2-{[(5 -chloropyridin-2-yl)amino]carbonyl}-3-[({trans-4-[(dimethylamino)carbonyl]cyclohexyl}carbonyl)amino]benzofuran-5-carboxylate;

Methyl [2- {[(5-chloropyridin-2-yl)amino]carbonyl}-3-({[trans-4-(pyrrolidin- 1-ylcarbonyl)cyclohexyl]carbonyl}amino)benzofuran-5-yl]acetate;

N 2 -(5-Chloropyridin-2-yl)-N 5 ,N 5 -dimethyl-3 -({[trans-4-(morpholin-4-ylcarbonyl)cyclohexyl]carbonyl}amino)-benzofuran-2,5-dicarboxamide;

N-(5-Chloropyridin-2-yl)-3-[(5-morpholin-4-yl -5-oxopentanoyl)amino]benzofuran-2-carboxamide;

2- {[(5-Chloropyridin-2-yl)amino]carbonyl}-3-[({trans-4-[(dimethylamino)carbonyl]cyclohexyl}carbonyl)amino]-benzofuran-5-carboxylic acid;

N 2 -(5-Chloropyridin-2-yl)-3-[({trans-4-[(dimethylamino)carbonyl]cyclohexyl}carbonyl)amino]-N 5 ,N 5 -dimethylbenzofuran-2,5-dicarboxamide;

trans-N′-[2-{[(5-Chloropyridin-2-yl)amino]carbonyl}-5-morpholin-4-ylcarbonyl)benzofuran-3-yl]-N,N-dimethylcyclohexane- 1,4-dicarboxamide, or

a pharmaceutically acceptable-salt thereof.

18. A pharmaceutical composition, which comprises as an active ingredient a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

19. A method for treatment of thrombosis, which comprises administering an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a patient in need thereof.